1. Field of the Invention
The present invention provides compounds, compositions, kits, and methods comprising drugs, medical foods, and dietary supplements for the prevention and treatment of metabolic disorders, in particular, insulin resistance syndromes, diabetes, obesity, weight gain, hyperlipidemia, fat maldistribution, cardiovascular disease and osteoporosis resulting from general inflammation or HIV-1 infection. More specifically, the invention relates to anti-inflammatory, pharmaceutical compositions and therapeutic methods utilizing such compositions to modify adipocyte physiology to enhance insulin sensitivity.
2. Description of the Related Art
Research has implicated dysregulated inflammatory processes in the pathogenesis of many prevalent, chronic diseases including metabolic syndrome, insulin resistance, diabetes, obesity, dyslipidemia, lipodystrophy and cardiovascular disease. Increased plasma concentrations of tumor necrosis factor alpha (TNFα), interleukin-6 (IL-6), C-reactive protein (CRP) and plasminogen activator inhibitor-1 (PAI-1), which are characteristic of chronic inflammation, are found in varying degrees in all of these pathologies [Dandona, P., et al. Inflammation: the link between insulin resistance, obesity and diabetes. Trends Immunol. 25(1):407, (2004); Dandona, P. Endothelium, inflammation, and diabetes. Curr Diab Rep 2(4):311-315, (2002)]. As such, anti-inflammatory directed treatment modalities have the potential to provide therapeutic or palliative benefits for these conditions.
Insulin resistance is now well recognized as a chronic inflammatory state. The interrelationship between inflammation and inflammatory mediators and the diabetic state, whether insulin dependent or independent, has long been noted. For example, insulin dependent diabetes mellitus (IDDM) is characterized by an initial inflammatory response or cellular infiltration in or around the pancreatic islet cells [Gepts, W. Pathologic anatomy of the pancreas in juvenile diabetes mellitus. Diabetes 14: 619-633, (1965); see also Koliopanos, A., et al., Cyclooxygenase 2 expression in chronic pancreatitis: Correlation with stage of the disease and diabetes mellitus. Digestion 64: 240-247, (2001); and Luo, C., et al., Cellular distribution and contribution of cyclooxygenase (COX)-2 to diabetogenesis in NOD mouse. Cell Tissue Res. 310: 169-175, (2002)].
The concept of inflammation and adipocyte interaction in relation to these metabolic conditions started with a seminal publication by Hotamisligil et al. in 1993, which demonstrated that adipocytes constitutively express the pro-inflammatory cytokine TNFα, and that TNFα expression in the adipocytes of obese animals (ob/ob mouse, db/db mouse and fa/fa Zucker rat) is markedly increased. Further, neutralization of TNFα by soluble TNFα receptor leads to a decrease in insulin resistance in these animals [Hotamisligil G. S., et al. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259:87-91, (1993)]. These observations provide a link between an increase in the expression and plasma concentration of a pro-inflammatory cytokine and insulin resistance.
Clinical and experimental data developed since 1993 suggest that all major components of the metabolic syndrome including insulin insensitivity and obesity are associated with inflammatory conditions characterized by increased plasma concentrations of pro-inflammatory cytokines such as TNFα, IL-6, C-reactive protein (CRP) and PAI-1 [Yudkin, J. S., et al. C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue? Arterioscler. Thromb. Vasc. Biol. 19:972-978, (1999); Mohamed-Ali, V., et al. Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-a, in vivo. Endocrinol. Metab. 82:4196-4200, (1997); Lundgren, C. H., et al. Elaboration of type-1 plasminogen activator inhibitor from adipocytes. A potential pathogenetic link between obesity and cardiovascular disease. Circulation 93:106-110, (1996)]. Clinically, it has been shown that human adipose tissue expresses TNFα constitutively and that expression falls after weight loss [Kern, P. A., et al. The expression of tumor necrosis factor in human adipose tissue. Regulation by obesity, weight loss, and relationship to lipoprotein lipase. J. Clin. Invest. 95:2111-2119, (1995)].
The prevalence of diabetes mellitus has increased roughly in parallel with that of obesity, which has itself doubled in the United States in the last twenty years. Some experts have stated that obesity in the United States is an epidemic. In any case, as the population ages, it is likely that the rate of obesity will increase with time. The correlation between obesity and diabetes is manifest, as are the correlations between cardiovascular disease and both obesity and diabetes. A non-obese, type two diabetic is far more likely to suffer from cardiovascular disease than is a non-obese, non-diabetic; and an obese non-diabetic is at an even higher risk for cardiovascular disease than is a non-obese diabetic. Thus, in addition to inflammation, there are apparently causal links between cardiovascular disease and both obesity and diabetes.
It is now generally accepted that adipose tissue acts as an endocrine organ producing a number of biologically active peptides with an important role in the regulation of food intake, energy expenditure and a series of metabolic processes. Adipose tissue secretes a number of bioactive peptides collectively termed adipokines. Through their secretory function, adipocytes lie at the heart of a complex network capable of influencing several physiological processes (FIG. 1). Dysregulation of adipokine production with alteration of adipocyte mass has been implicated in metabolic and cardiovascular complications of obesity. In obese individuals, excessive production of acylation-stimulating protein (ASP), TNFα, IL-6 or resistin deteriorates insulin action in muscles and liver, while increased angiotensinogen and PAI-1 secretion favors hypertension and impaired fibrinolysis. Leptin regulates energy balance and exerts an insulin-sensitizing effect. These beneficial effects are reduced in obesity due to leptin resistance. Adiponectin increases insulin action in muscles and liver and exerts an anti-atherogenic effect. Further, adiponectin is the only known adipokine whose circulating levels are decreased in the obese state. The thiazolidinedione anti-diabetic drugs increase plasma adiponectin, supporting the idea that adipokine-targeted pharmacology represents a promising therapeutic approach to control type 2 diabetes and cardiovascular diseases in obesity (FIG. 2) [Guerre-Millo, M. Adipose tissue and adipokines: for better or worse. Diabetes Metabolism 30:13-19, (2004)].
Insulin resistance and/or hyperinsulinemia have been postulated to be the cause of the other abnormal metabolic and cardiovascular risk factors that occur in the metabolic syndrome (FIG. 3). These risk factors have been identified as (1) central obesity (including increased visceral fat); (2) a characteristic dyslipidemia that includes an elevated plasma triglyceride, a low plasma high-density lipoprotein (HDL), and a small dense low-density lipoprotein (LDL) cholesterol particle pattern; (3) a procoagulant state made up of elevated plasma fibrinogen and plasminogen activator inhibitor-1; (4) elevated systolic and diastolic blood pressure; (5) hyperuricemia; and (6) microalbuminuria [Lebovitz, H. E., and Banerji, M. A. Insulin resistance and its treatment by thiazolidinediones. Recent Prog Horm Res. 56:265-94, (2001)].
One method for the treatment of insulin resistance is with oral antihyperglycemic agents. Oral antihyperglycemic agents can be classified into six, distinct classes based upon mechanism of action: (1) biguanides, such as metformin, that decrease hepatic glucose production; (2) sulfonylureas such as glipizide, glyburide, and glimepiride, and (3) nonsulfonylureas such as repaglinide and nateglinide that increase pancreatic insulin secretion; (4) α-glucosidase inhibitors, with acarbose being the only representative on the market, that delay intestinal carbohydrate absorption; (5) thiazolidinediones, rosiglitazone and pioglitazone, agents that increase fatty acid uptake of adipocytes as well as glucose uptake in both muscle and fat; and 6) anti-inflammatories (e.g. aspirin (not used due to toxicity associated with the levels necessary to improve glucose control)) [Scheen, A. J. Drug treatment of non-insulin-dependent diabetes mellitus in the 1990s. Achievements and future developments. Drugs 54(3):355-368, (September 1997); Scheen, A. J. and Lefebvre, P. J. Antihyperglycaemic agents. Drug interactions of clinical importance. Drug Saf; 12(1):32-45, (January 1995); Inzucchi, S. E. Oral antihyperglycemic therapy for type 2 diabetes: scientific review. JAMA. 287(3):360-372, (Jan. 16, 2002); and Gao, Z., et al. Aspirin inhibits serine phosphorylation of insulin receptor substrate 1 in tumor necrosis factor-treated cells through targeting multiple serine kinases. J. Bio. Chem. 278(27): 24944-24950, (2003)].
With few exceptions, the available antidiabetic drugs are equally effective at lowering glucose concentrations. Due to their differing mechanisms of action, they appear to have distinct metabolic effects as reflected in their effect on cardiovascular risk and adverse effect profiles. Metformin currently is the only drug associated with weight loss (or no effect on body weight); it has become the most widely prescribed single hyperglycemic drug and is generally regarded as the best first-line agent especially in the obese patient without contraindications for its use.
Failure to maintain adequate blood glucose for extended periods, however, is frequently seen independent of choice of drug. For example, sulphonylureas have a secondary failure rate of up to 10% each year. This associated worsening hyperglycemia often necessitates the use of polypharmacy; i.e. three years after diagnosis, approximately half of patients require more than one pharmaceutical agent and within nine years this increases to 75% of all patients [Turner, R. C., Cull, C. A., Frighi, V., and Holman, R. R. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS) Group. JAMA. 281(21):2005-2012, (Jun. 2, 1999)]. Moreover, despite the use of combination therapy physicians generally do not reach targets for glycemic control [Zinman, B. PPARgamma agonists in type 2 diabetes: how far have we come in preventing the inevitable'? A review of the metabolic effects of rosiglitazone. Diabetes Obes Metab. 3 Suppl 1:34-43, (August 2001)].
Statistics on the increasing incidence of NIDDM and the rate of therapeutic failures in maintaining adequate blood glucose indicate that new approaches in the treatment of NIDDM and its complications are important public health priorities. Although diet, regular exercise and weight control have proven effective for modifying the pathogenesis of insulin resistance and increasing the efficacy of antidiabetic drugs, it can be anticipated that a majority of persons will eschew dietary modifications and exercise and that monotherapy will ultimately fail to adequately control the myriad of metabolic imbalances manifest in NIDDM. In light of the tremendous cost of NIDDM, both in terms of human suffering and monetary resources, it seems highly desirable to have additional agents to support treatment [McCarty, M. F. Nutraceutical resources for diabetes prevention—an update. Med. Hypotheses. 64(1):151-158, (2005); McCarty, M. F. Toward practical prevention of type 2 diabetes. Med. Hypotheses. 54(5):786-793, (May 2000)].
In addition to diabetes, obesity and cardiovascular disease, other conditions are now recognized as inflammatory pathologies. These include (1) diseases of the digestive organs such as ulcerative colitis, Crohn's disease, pancreatitis and gastritis; (2) proliferative diseases, such as benign tumors, polyps, hereditary polyposis syndrome, colon cancer, rectal cancer, breast cancer, prostate cancer, and stomach cancer; and (3) ulcerous disease of the digestive organs, and (4) cardiovascular pathologies including stenocardia, atherosclerosis, myocardial infarction, sequelae of stenocardia or myocardial infarction, senile dementia, and cerebrovascular diseases. Further, chronic HIV-1 infection is now recognized as an inflammatory pathology related to alterations in glucose and lipid metabolism.
As in the case with many other infections, HIV infection is accompanied by disturbances in lipid and glucose metabolism. These metabolic abnormalities are further confounded by hypercholesterolemia and hypertriglyceridemia induced by anti-retroviral (AR) drugs. It has been estimated that almost two-thirds of HIV/AIDS patients exhibit abnormal fat distribution coincident with AR-therapy (ART). Clinicians have termed this abnormal fat distribution lipodystrophy or fat maldistribution. Although various terms have been used, the term both lipodystrophy and fat maldistribution will be used here interchangeably to describe the syndrome of body shape changes related to changes in fat distribution in people with HIV/AIDS receiving AR-therapy (HIV/ART).
Various descriptions have been proposed for the morphologic abnormalities and the metabolic alterations that appear to be associated with fat maldistribution. While clinicians have a general understanding of changes in fat distribution occurring in persons with HIV, no consensus exists among them on the clinical measures used to define fat maldistribution. When questioned, physicians generally describe a syndrome of “maldistribution of body fat,” “buffalo hump,” “thinning of arms and legs,” “facial thinning,” and/or “increases in abdomen size.” Few physicians mention metabolic markers when defining fat maldistribution.
“Lipo” refers to fat and “dystrophy” means abnormal growth. Before being recognized in HIV-infected patients, the lipodystrophies were described as rare abnormalities of adipose tissue characterized by body shape changes and metabolic abnormalities, including insulin resistance, hyperglycemia, and hyperlipidemia.
Although there appear to be some similarities between the established lipodystrophies seen prior to HIV and that seen in HIV/ART patients, there is little evidence of fat accumulation or maldistribution as being a common presentation in persons with lipodystrophy before the development of successful ART combinations for HIV. The fat maldistribution with HIV/AR-related lipodystrophy is typically a mix of central fat accumulation and peripheral fat loss, and this pattern does not seem to fit readily into any definition of previously described lipodystrophies.
Historically, before HIV, lipodystrophy was used to describe features of lipoatrophy only. The use of this term to describe features of fat accumulation as well as fat loss in HIV/ART-patients helped to initiate the confusion, which still exists, on the clinical case definition of HIV/ART-related lipodystrophy. Nevertheless, it is now accepted that the lipodystrophy seen in patients with HIV infection receiving ART is a syndrome involving physical and metabolic abnormalities.
The physical changes associated with the HIV/ART lipodystrophy syndrome can be divided into two major types, both of which involve an abnormal or maldistribution of body fat: lipoatrophy or fat wasting and lipohypertrophy or fat accumulation. An increase in abdominal girth is a common complaint in patients, while thinning of the extremities is also frequently seen, often with prominence of the veins in the arms and legs (cabling) due to subcutaneous fat loss. A substantial proportion of patients report increased wrinkling of the skin with a loss of subcutaneous tissue in the cheeks and around the nose and lips.
Abnormal metabolic changes include altered lipid metabolism manifest by increased triglycerides, increased total cholesterol and increased low-density lipoprotein (LDL) cholesterol. Alterations in glucose metabolism with lipodystrophy include insulin resistance, impaired glucose tolerance and NIDDM.
Although surgery is sometimes elected to remove unsightly fat deposits and restore normal facial appearance, the most frequently prescribed drugs for maintaining normal body composition are recombinant human growth hormone (Somatotrophin®) and anabolic steroids (e.g. Oxandrin®). Other adjunctive measures, such as progressive resistance exercises may also be utilized. Cosmetic surgery appears to be only a stopgap measure and patients frequently continue abnormal body fat deposition. The medications described are highly effective in many patient groups. However, human growth hormone is costly and anabolic steroids may present significant hepatic and cardiovascular risk to the HIV patient.
Among the dietary supplements sold to promote body composition changes, N-acetylcysteine (NAC), L-carnitine, acetyl-L-carnitine, arginine and omega-3 fatty acids have been suggested for wasting and lipodystrophy in HIV/AIDS. No positive data have yet been developed to support these recommendations.
The role of NAC in HIV has been examined since 1989 in 16 peer-reviewed publications (Breitkreutz R, et al. Improvement of immune functions in HIV infection by sulfur supplementation: two randomized trials [see comments]. J Mol Med 2000; 78(1):55-62; Akerlund B, et al. N-acetylcysteine treatment and the risk of toxic reactions to trimethoprim-sulphamethoxazole in primary Pneumocystis carinii prophylaxis in HIV-infected patients. J Infect 1997; 35:143-147; Jahoor F, et al. Erythrocyte glutathione deficiency in symptom-free HIV infection is associated with decreased synthesis rate. Am J Physiol 1999; 276:E205-E211; Walmsley S L, et al. A randomized trial of N-acetylcysteine for prevention of trimethoprim-sulfamethoxazole hypersensitivity reactions in Pneumocystis carinii pneumonia prophylaxis (CTN 057). Canadian HIV Trials Network 057 Study Group. J Acquir Immune Defic Syndr Hum Retrovirol 1998; 19(5):498-505; Look M P, et al. Sodium selenite and N-acetylcysteine in antiretroviral-naive HIV-1-infected patients: a randomized, controlled pilot study. Eur J Clin Invest 1998; 28:389-397; Herzenberg L A, et al. Glutathione deficiency is associated with impaired survival in HIV disease. Proc Natl Acad Sci USA 1997; 94:1967-1972; Akerlund B, et al. Effect of N-acetylcysteine (NAC) treatment on HIV-1 infection: a double-blind placebo-controlled trial. Eur J Clin Pharmacol 1996; 50:457-461; Witschi A, et al. Supplementation of N-acetylcysteine fails to increase glutathione in lymphocytes and plasma of patients with AIDS. AIDS Res Hum Retroviruses 1995; 11:141-143; de Quay B, et al. Glutathione depletion in HIV-infected patients: role of cysteine deficiency and effect of oral N-acetylcysteine. AIDS 1992; 6:815-819; De Rosa S C, et al. N-acetylcysteine replenishes glutathione in HIV infection. Eur J Clin Invest 2000; 30:915-929; Muller F, et al. Virological and immunological effects of antioxidant treatment in patients with HIV infection. Eur J Clin Invest 2000; 905-914; Kinscherf R, et al. Effect of glutathione depletion and oral N-acetyl-cysteine treatment on CD4+ and CD8+ cells. FASEB J 1994; 8:448-451; Bogden J D, et al. Status of selected nutrients and progression of human immunodeficiency virus type 1 infection. Am J Clin Nutr 2000; 72:809-815; Skurnick J H, et al. Micronutrient profiles in HIV-1-infected heterosexual adults. J Acquir Immune Defic Syndr Hum Retrovirol 1996; 12:75-83; Bogden J D, et al. Micronutrient status and human immunodeficiency virus (HIV) infection. Ann NY Acad Sci 1990; 587:189-[95]. Due to its history of safe use as a therapeutic, NAC has been suggested as a potential supplement for glutathione replenishment in HIV since 1991 (Droge W, et al. Modulation of lymphocyte functions and immune responses by cysteine and cysteine derivatives. Am J Med 1991; 91:140 S-144S; Mihm S, et al. Inhibition of HIV-1 replication and NF-kappa B activity by cysteine and cysteine derivatives. AIDS 1991; 5:497-503; Harakeh S, and Jariwalla R J. Comparative study of the anti-HIV activities of ascorbate and thiol-containing reducing agents in chronically HIV-infected cells. Am J Clin Nutr 1991; 54:1231S-1235S). While NAC has demonstrated several positive effects for people living with HIV, no research studies have reported that treatment of HIV-infected persons with NAC alone, or in combination with other nutrients or drugs, can successfully ameliorate fat maldistribution or hyperlipidemia.
Research on fatty acids in HIV has been generally limited and only one clinical trial has been reported on HIV wasting and fatty acid supplementation. A combination consisting of omega-3 fatty acids and arginine was clinically tested for its ability to affect weight gain and blood lipid levels in HIV/ART patients (Sudre, P C, et al. A randomized double-blind controlled study of 6 months of oral nutritional supplementation with arginine and omega-3 fatty acids in HIV-infected patients. Swiss HIV Cohort Study. 1998 AIDS 12 (1)53-63). Sixty-four HIV-infected outpatients with CD4 counts greater than or equal to 100 μL were randomized to receive 7.4 g arginine plus 1.7 g omega-3 fatty acids or placebo daily. Gain in body weight and fat mass were approximately 2 and 1 kg, respectively in both treatment and placebo groups. Thus, enrichment of an oral nutritive supplement with arginine and omega-3 fatty acids did not improve weight gain or fat-free mass in HIV/ART patients. Such results imply that fatty acid supplementation alone, or in certain obvious combinations, are unlikely to positively affect fat distribution or hyperlipidemia in HIV/ART patients.
Inflammatory mediated metabolic disorders such as fasting hyperlipidemia and fasting hyperglycemia are prevalent among HIV-infected individuals receiving ART. Morphological changes accompany these inflammatory mediated metabolic disorders and have been termed lipodystrophy syndrome. Affected individuals show fat redistribution, such as fat loss (e.g., in face) or fat accumulation (e.g., in abdominal area). These metabolic disorders are generally attributed to ART. Left untreated, the downstream adverse consequences of fat maldistribution include atherogenesis and atherosclerotic vascular disease. Thus, there is a critical need to provide nutritional supplementation to manage these metabolic and morphologic disorders. At this time, there are no safe and efficacious nutritional products that can normalize metabolic or body changes in HIV/ART-patients.
Thus, it is to be expected that effective anti-inflammatory based methods of improving insulin sensitivity will be useful in the treatment, prevention or delay of onset of one or more of the foregoing inflammatory disorders. Dietary based anti-inflammatory compounds and extracts represent an as yet underutilized source for palliative or preventive treatment modalities.